Department of Biochemistry, School of Life Sciences (SLS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
Computer Aided Therapeutics and Drug Design (CATDD) Group, School of Sciences (SOS), Federal University of Technology Akure, P.M.B 704, Akure, Nigeria.
Sci Rep. 2024 Oct 23;14(1):24995. doi: 10.1038/s41598-024-74851-1.
Ubiquitin-specific peptidase 7 (USP7) is a deubiquitinating enzyme that mediates the stability and activity of numerous proteins. At basal expression levels, USP7 stabilizes p53 protein, even in the presence of excess MDM2. However, its overexpression leads to the deubiquitination of MDM2 at a rate faster than p53, leading to p53 degradation and pro-tumorigenic roles. Consequently, it is an attractive target for anticancer drug discovery via the modulation of its allosteric site from which the protein is activated. In this study, molecular modeling techniques and cheminformatics approaches were employed to unravel the potential of eighty compounds to serve as its allosteric site modulators. The compounds were initially subjected to virtual screening. Subsequently, the binding free energies of the top four compounds with the highest binding affinities were calculated, and their drug-likeness, and pharmacokinetic and toxicity profiles were evaluated. Ultimately, the complexes of the protein and hit compounds were subjected to a 100 nanoseconds (ns) molecular dynamics simulation. The results of the study revealed eight compounds from the compound library with docking scores ranging from - 7.491 to -11.43 kcal/mol, compared to P217564, which exhibited a docking score of -5.671 kcal/mol. The top four compounds with the highest affinities possessed drug-like properties, and good pharmacokinetic and toxicity profiles, and their predicted inhibitory potentials showed they will be effective at minimal concentration. Also, molecular dynamics simulation confirmed the stability of the protein-ligand complexes. Conclusively, the compounds identified in this study are worthy of further evaluation for the development of allosteric site modulators of USP7.
泛素特异性肽酶 7（USP7）是一种去泛素化酶，可调节许多蛋白质的稳定性和活性。在基础表达水平下，USP7 稳定 p53 蛋白，即使在存在过量 MDM2 的情况下也是如此。然而，其过表达导致 MDM2 的去泛素化速度快于 p53，导致 p53 降解和促肿瘤作用。因此，通过调节其变构位点使蛋白激活，USP7 成为抗癌药物发现的有吸引力的靶标。在这项研究中，采用分子建模技术和化学信息学方法来揭示 80 种化合物作为其变构位点调节剂的潜力。这些化合物首先进行虚拟筛选。随后，计算了与结合亲和力最高的前四种化合物的结合自由能，并评估了它们的类药性、药代动力学和毒性特征。最后，将蛋白和命中化合物的复合物进行了 100 纳秒（ns）分子动力学模拟。研究结果表明，与 docking score 为-5.671 kcal/mol 的 P217564 相比，从化合物库中筛选出 8 种化合物，其 docking score 范围为-7.491 至-11.43 kcal/mol。具有最高亲和力的前四种化合物具有类药性，良好的药代动力学和毒性特征，其预测的抑制潜力表明它们将在最小浓度下有效。此外，分子动力学模拟证实了蛋白-配体复合物的稳定性。总之，本研究中鉴定的化合物值得进一步评估，以开发 USP7 的变构位点调节剂。
